Biology subjects

Hicheri, Y.

Publications and source records attributed to Hicheri, Y..

3 recordsLinked to original sources

bioRxiv2022

SUMOylation controls the rapid transcriptional reprogramming induced by anthracyclines in Acute Myeloid Leukemias

Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR), one of the main drugs used to treat Acute Myeloid Leukemia (AML), induces broad transcriptional changes in AML cells before cell death induction. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, which limits both the positive and negative effects of DNR on transcription. Quantitative proteomics shows that proteins that are deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. Its induction is preceded by a SUMO-dependent reconfiguration of chromatin loops engaging its CTCF- and SUMO-bound promoter with distal cis-regulatory regions. Altogether, our work suggests that one of the earliest effects of DNR in AML cells is a SUMO-dependent transcriptional reprogramming.

molecular biology↗

bioRxiv2019

Ubiquitin and SUMO conjugation as biomarkers of Acute Myeloid Leukemias response to chemotherapies

Ubiquitin and the ubiquitin-like SUMO are covalently conjugated to thousands of proteins to modulate their function and fate. Many of the enzymes involved in their conjugation are dysregulated in cancers and involved in cancer cells response to therapies. We describe here the identification of biomarkers of the activity of these enzymes and their use to predict Acute Myeloid Leukemias (AML) response to standard chemotherapy (daunorubicine-DNR and cytarabine-Ara-C). We compared the ability of extracts from chemosensitive and chemoresistant AML cells to conjugate ubiquitin or SUMO-1 on 9000 proteins spotted on protein-arrays. We identified 122 proteins whose conjugation by these post-translational modifiers marks AML resistance to DNR and/or Ara-C. Based on this modifomic signature, we defined a statistical score able to predict AML patient response to standard chemotherapy. We finally developed a miniaturized assay to easily assess the modification level of the selected biomarkers and validated it in patient cell extracts. Thus, our work identifies a new type of ubiquitin-based biomarkers that could be used to predict cancer patients response to treatments.\n\nSummary blurbThis study describes the identification of a new class of biomarkers of cancer response to therapies based on protein modification by Ubiquitin and SUMO and provides the tools to analyze them in Acute Myeloid Leukemia patient samples.

cancer biology↗

bioRxiv2018

Targeting the SUMO pathway primes all-trans-retinoic acid-induced differentiation of non promyelocytic Acute Myeloid Leukemias

Differentiation therapies using All-trans-retinoic acid (ATRA) are highly efficient at treating Acute Promyelocytic Leukemia (APL), a minor subtype of Acute Myeloid Leukemias (AML). However, their efficacy, if any, is very limited in the case of non-APL AMLs. We report here that the inhibition of SUMOylation, a post-translational modification related to ubiquitinylation, restores the pro-differentiation and anti-proliferative activities of retinoids in non-APL AMLs. Controlled inhibition of SUMOylation with pharmacological inhibitors (2-D08 or anacardic acid), or via overexpression of SENP desumoylases, strongly enhances the ATRA-induced expression of key genes involved in differentiation, proliferation and apoptosis in non-APL AML cells. This activates ATRA-induced terminal myeloid differentiation and reduces cell proliferation and viability, including in AML cells resistant to chemotherapeutic drugs. Conversely, enhancement of SUMOylation by overexpressing the SUMO-conjugating enzyme Ubc9 dampens the expression of ATRA-responsive genes and prevents differentiation. Thus, inhibition of the SUMO pathway is a promising strategy to sensitize non-APL AML patients to retinoids and improve the treatment of this poor prognosis cancer, which has not significantly changed over the past 40 years.

cancer biology↗